The major objectives of this research are to isolate the agent responsible for CFS and to define the immune disorders associated with this disease. Blood will be examined for replication of an infectious agent and for antibodies to an agent recovered from the peripheral blood mononuclear cells (PBMC) or body fluids of CFS patients. Cell culture studies will utilize procedures for detecting viruses including hemabsorption, hemagglutination, reverse transcriptase (RT) and immunofluorescence assays. In addition, the PBMC from individuals with CFS will be evaluated by polymerase chain reaction (PCR) for the presence of cross- reacting genetic material using selected regions of human retroviruses and herpesviruses. Identification of the agent as one associated with CFS will be documented by serologic studies using sera from CFS patients and the ability of the agent to induce the immune abnormalities observed. The immunologic studies proposed will involve comparison of the cell surface markers on peripheral white cells of CFS patients to those of controls as well as patients with other viral infections, depression and autoimmunity. At present, the results indicate that the CD8+ cell subset in CFS patients is unusual in its high percentage of activation markers on the cell surface and the reduction of CD8+ suppressor cells (CD11b+). These observations suggest a chronic hyperactivity of the immune system of CFS patients. Immune function will be evaluated by assays of lymphocyte and NK cell activities as well as cytokine production. Increased production of some of these cellular products could be responsible for the symptoms observed in CFS.